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Immune complexes as for autoimmunity

Raphael Clynes

J Clin Invest. 2005;115(1):25-27. https://doi.org/10.1172/JCI23994.

Commentary

For several decades, intravenous Ig has been used as treatment for a variety of immune-related , including immune thrombocytopenic purpura (ITP), autoimmune neuropathies, systemic erythematosus, , Guillain-Barré syndrome, skin blistering syndromes, and Kawasaki . Despite years of use, its mechanism of immunomodulation is still unclear. Recent studies using mouse models of ITP and , including one reported in this issue of the JCI, now provide some insights into this mechanism and the rationale for the development of Fcγ – targeted therapeutics.

Find the latest version: https://jci.me/23994/pdf commentaries this is most welcome, particularly for science that appears to promise so much 4. Studer, L., Tabar, V., and McKay, R.D. 1998. Trans- plantation of expanded mesencephalic precursors investigators working on strategies for cell for the treatment of human diseases. leads to recovery in parkinsonian rats. Nat. Neurosci. replacement the United States, who must 1:290–295. be feeling something of a déjà vu in face Address correspondence to: J. William 5. Isacson, O., et al. 2001. Cell implantation of yet another presidential moratorium, Langston, The Parkinson’s Institute, for Parkinson’s disease using neural stem, trans- genic or xenogeneic donor cells. Parkinsonism Relat. this time limiting the number of human 1170 Morse Avenue, Sunnyvale, Cali- Disord. 7:205–212. stem cell lines that can be used for research fornia 94089-1605, USA. Phone: (408) 6. Sanchez-Pernaute, R., Studer, L., Bankiewicz, K.S., and treatment. Ironically, this frustration 734-2800; Fax: (408) 734-8522; E-mail: Major, E.O., and McKay, R.D. 2001. In vitro genera- tion and transplantation of precursor-derived human recently led California voters to approve [email protected]. dopamine neurons. J. Neurosci. Res. 65:284–288. a $3 billion initiative to fund stem cell 7. Kim, J.H., et al. 2002. Dopamine neurons derived research, which some have predicted will 1. Freed, C.R., et al. 2001. Transplantation of embry- from embryonic stem cells function in an animal lead to a “gold rush” on stem cell research onic dopamine neurons for severe Parkinson’s model of Parkinson’s disease. Nature. 418:50–56. disease. N. Engl. J. Med. 344:710–719. 8. Takagi, Y., et al. 2005. Dopaminergic neurons gen- (9). Regardless of whether or not this 2. Olanow, C.W., et al. 2003. A double-blind con- erated from monkey embryonic stem cells func- proves to be the case, it can be hoped that trolled trial of bilateral fetal nigral transplantation tion in a Parkinson primate model. J. Clin. Invest. this new initiative will serve as a beacon of in Parkinson’s disease. Ann. Neurol. 54:403–414. 115:102–109. doi:10.1172/JCI200521137. 3. Kordower, J.H., and Sortwell, C.E. 2000. Neuro- 9. Holden, C. 2004. U.S. science policy. California’s hope for scientists and patients alike as pathology of fetal nigra transplants for Parkinson’s Proposition 71 launches stem cell gold rush. Sci- we press ahead in this challenging area of disease. Prog. Brain Res. 127:333–344. ence. 306:1111. Immune complexes as therapy for autoimmunity Raphael Clynes

Department of Medicine and Microbiology, Columbia University, New York, New York, USA.

For several decades, intravenous Ig has been used as treatment for a variety dependent , whereas the mac- of immune-related diseases, including immune thrombocytopenic purpura rophage responsible for FcγRIII-mediated (ITP), autoimmune neuropathies, systemic , myasthe- platelet clearance is CSF-1 independent (8). nia gravis, Guillain-Barré syndrome, skin blistering syndromes, and Kawa- Thus, while other targets may prove effective saki disease. Despite years of use, its mechanism of immunomodulation in the treatment of –related is still unclear. Recent studies using mouse models of ITP and arthritis, (IC-related) autoimmunity (9, 10), at least 2 including one reported in this issue of the JCI (see the related article begin- distinct FcγR therapeutic approaches are ning on page 155), now provide some insights into this mechanism and the tenable: direct blockade of the phagocytic Fc rationale for the development of Fcγ receptor–targeted therapeutics. receptors and IVIg-triggered, FcγRIIB-medi- ated inhibition (Figure 1). Fc receptors in the pathogenesis tive therapy in ITP. Indeed, this has proven and treatment of ITP to be a valid approach; that block What is the active component Intravenous Ig (IVIg) is remarkably FcγRIII have been shown to be effective in of IVIg and intravenous anti-D? effective in the treatment of immune murine studies (2, 4) as well as in pilot clini- A related therapeutic, intravenous anti-D, has thrombocytopenic purpura (ITP), with cal studies (5). also been highly effective in ITP, but only in improved platelet counts seen in 80% of Although activating Fc receptor blockade is Rh+ patients. The active component is clearly treated patients. ITP occurs in patients as the an appealing mechanism, a second, unexpect- anti-D antibodies that generate large par- result of the generation of ed FcγR-related pathway is clearly relevant to ticulate ICs, namely opsonized rbcs, in Rh+ that bind to platelet surface . These the therapeutic action of IVIg. It was recently patients. In contrast, the active components opsonized platelets are phagocytosed by shown (4) that the protective effect of IVIg is in IVIg, a product obtained from sera pooled Fc receptor–bearing splenic and hepatic associated with upregulation of the inhibito- from thousands of donors, could conceiv- macrophages (1). In the mouse, macro- ry receptor FcγRIIB on splenic macrophages ably include a variety of Fc receptor–binding phage-mediated clearance occurs via acti- and is abrogated in mice lacking FcγRIIB. ligands. In addition to the dominant species vating Fc receptors, with complement-medi- Curiously, this effect is independent of SHIP of monomeric IgG (which would bind FcRn ated uptake playing little or no role (2, 3). and SHP-1 (6), the 2 downstream inhibi- and the high-affinity FcγRI), multiple types Thus, blockade of activating Fcγ receptors tory phosphatases previously assumed to of ICs, which bind all Fc receptors, are likely (FcγRs) would be predicted to be an effec- be responsible for the inhibitory signaling to form in vivo after the administration of pathway. Redundant functions of SHIP and IVIg. These complexes of varying valencies Nonstandard abbreviations used: FcγR, Fcγ receptor; SHP-1 or other phosphatases downstream include cell-associated and soluble host IC, immune complex; ITP, immune thrombocytopenic of FcγRIIB may be responsible (7), but as yet antigens bound by donor natural antibodies purpura; IVIg, intravenous Ig. the FcγRIIB-mediated signal is unclear. Add- as well as dimers and aggregated Igs formed Conflict of interest: The author has declared that no conflict of interest exists. ing further to the mystery is the observation in the IVIg product itself. Using mimetic Citation for this article: J. Clin. Invest. 115:25–27 that 2 distinct populations are modeling studies, Siragam et al. (11) suggest (2005). doi:10.1172/JCI200523994. involved; IVIg protection requires CSF-1– that the 2 therapeutics IVIg and anti-D have

The Journal of Clinical Investigation http://www.jci.org Volume 115 Number 1 January 2005 25 commentaries

Targeting FcγRIIB directly by cross-linking FcγRIIB-specific antibodies has been shown to be beneficial in the mouse model of ITP, and injection of small, preformed ICs is also protective (18). The current work provides another potential solution, namely injection of antibodies with specificities for serum proteins including albumin and transferrin, which provide FcγRII-dependent protection (11). Monoclonal antibodies recognizing a single form monomeric ICs, imply- ing that clustering of FcγRs by these small ICs is not required for their therapeutic effect. Even with polyclonal α-albumin or α-transferrin antibodies, the resultant ICs formed in vivo are still likely to be quite small, since the serum target proteins are present in such large molar excess. While this is an intriguing approach, an obvious concern is the potential for untoward IC- triggered responses, which might complicate its clinical use.

Implications for other autoimmune states Siragam et al. extend their observa- tions beyond -mediated thrombocytopenia in showing that both IVIg and its mimetic anti-murine albumin antibodies protect in the K/BxN serum– induced arthritis model (11). The clinical Figure 1 benefit of IVIg has been spotty in autoim- Inhibition of phagocytosis in vivo can be accomplished via IC-mediated inhibition of FcγR func- tional activity. These complexes, varying in size and valency, operate through distinct mechanis- mune conditions, such as rheumatoid tic pathways. IVIg leads to the formation of variably sized ICs, including small monomeric and arthritis (19–24), in which autoaggressive T dimeric complexes. The small ICs (Ig dimers or soluble /donor Ig complexes) require cells are believed to be the culprits. Recent CSF-1–dependent macrophages and FcγRII expression to mediate their as-yet-undefined anti- attention in these –mediated diseases, inflammatory effect. Intravenous anti-D generates large particulate ICs, namely opsonized rbcs. however, has been redirected toward the role These large ICs induce a phagocytic block in vivo in a manner independent of FcγRII expression. of humoral in the activation of T Perhaps mimicking the situation directly, antibodies that specifically engage either the inhibitory cells (25). Further, deficiency of activating FcγRII (4) or the activating FcγRIII (4, 5) can also induce platelet count recovery. FcγRs has been shown to be protective in classical T cell–mediated diseases, including arthritis (20–24) and experimental autoim- distinct mechanisms of action, either via rbcs. However, the fact that large increases mune encephalomyelitis (26–29), which sug- small, soluble ICs or via large, particulate ICs. in platelet counts are achieved with anti-D gests that FcγR-based therapeutics might The protective capacity of small ICs was with little concomitant induction of have as-yet-undiscovered clinical activity in found to be FcγRIIB dependent, which (13) suggests that there are other contribut- T cell–mediated autoimmune conditions recapitulated results seen previously with ing mechanisms, including induction of through regulatory effects on FcγR-bear- the IVIg effect (4). This suggests that in and downregulation of activating ing antigen-presenting cells. Identifying the contrast to anti-D, small ICs likely mediate FcγRIII (Figure 1) (12, 14–17). critical FcγR mechanistic pathways hinted at IVIg protection. In contrast, as reported else- by studies of IVIg may prove helpful in gen- where (12), opsonized rbcs (anti-OVA/OVA- New approaches to Fc erating more effective pharmacologic agents coupled rbcs) were capable of protecting receptor therapeutics and could widen the circle of patients pos- against platelet clearance in both normal The implication is that IVIg is far from an sibly benefiting from FcγR-targeted thera- and FcγRIIB-deficient mice, which suggests optimized therapeutic. Thus, in addition to peutics. Thus, other -driven that they interfere directly with activating theoretical and practical concerns regard- diseases, beyond ITP, may prove treatable FcγR–mediated phagocytosis. The FcγRIIB- ing safety, cost, and availability of this bio- with a little of what ails you. independent anti-inflammatory mechanism logic, a better understanding of how the of opsonized particulates might be assumed small IC component within IVIg exerts its Address correspondence to: Raphael Clynes, to be the straightforward result of activat- therapeutic impact will drive development Columbia University, P&S Building, RM ing FcγR blockade by antibody-coated of an improved pharmaceutical product. 8-510, 630 West 168th Street, New York,

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New York 10032, USA. Phone: (212) 10. Hansen, R.J., and Balthasar, J.P. 2002. Intravenous pooled intravenous immunoglobulin. . immunoglobulin mediates an increase in anti- 40:955–956. 305-5289; Fax: (212) 305-1392; E-mail: platelet antibody clearance via the FcRn receptor. 20. Diaz de Stahl, T., et al. 2002. Expression of Fcgam- [email protected]. Thromb. Haemost. 88:898–899. maRIII is required for development of collagen- 11. Siragam, V., et al. 2005. Can antibodies with speci- induced arthritis. Eur. J. Immunol. 32:2915–2922. 1. Alves-Rosa, F., et al. 2000. Treatment with ficity for soluble antigens mimic the therapeutic 21. Ioan-Facsinay, A., et al. 2002. FcgammaRI (CD64) liposome-encapsulated clodronate as a new stra- effects of intravenous IgG in the treatment of contributes substantially to severity of arthritis, tegic approach in the management of immune ? J. Clin. 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Terry Fox Laboratory, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.

Stromal cell–derived factor–1 (SDF-1) is a chemokine with unique func- the blood and bone marrow can also vary as tions, including a role in the trafficking of primitive blood precursor cells. a result of many perturbations and disease A better understanding at a molecular level of how the binding of SDF-1 to states. These include a variety of inflam- its cell surface receptor, CXCR4, elicits specific biological responses in these matory conditions, leukemias, myelosup- cells has now been achieved through the identification of PKC-ζ activation pressive treatments, and the administration as a common downstream signal. This finding suggests that treatment of a of pharmacologic doses of hematopoietic variety of clinical conditions might benefit from the targeting of PKC-ζ (see growth factors. All of these conditions the related article beginning on page 168). involve many physiological changes whose complexity has made it difficult to elucidate Overview of the regulation relatively small number of self-renewing the molecular events that regulate the traf- of stem/progenitor cell trafficking hematopoietic stem cells that turn over slow- ficking of primitive hematopoietic cells into Throughout adult life, the production of ly are also concentrated (1). In contrast, most and out of the bone marrow. blood cells is normally confined to par- of the cells circulating in the blood are highly One fruitful approach came from early ticular sites within bone cavities where a specialized cells with little or no proliferative analyses of the molecular interactions potential and a limited lifespan. However, between marrow stromal cells and primi- Nonstandard abbreviations used: PDK-1, phos- not all hematopoietic stem cells and their tive hematopoietic cells. This led to the phoinositide-dependent kinase–1; SDF-1, stromal primitive progeny are fixed in bone marrow identification of 2 pairs of molecular inter- cell–derived factor–1. niches. A small proportion of these cells con- actions that are important to the reten- Conflict of interest: The author has declared that no conflict of interest exists. tinuously enter the blood and then rapidly tion of primitive hematopoietic cells in the Citation for this article: J. Clin. Invest. 115:27–29 return to the marrow (2). The distribution bone marrow: VCAM-1 with very late anti- (2005). doi:10.1172/JCI200424013. of primitive hematopoietic cells between gen–4 (VLA-4) and membrane-bound Steel

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